ADAM proteins (a disintegrin and metalloproteinases) are multifunctional proteins involved in the ectodomain shedding of transmembrane proteins, cell adhesion and infiltration (non-patent documents 1, 2). The human genome contains 25 ADAMs including four pseudogenes and 21 kinds of ADAMs are composed of 13 kinds of proteolytic ADAMs that exhibit proteolytic activity and eight kinds of non-proteolytic ADAMs (non-patent documents 1, 3). Proteolytic ADAMs share the metalloproteinase domain of matrix metalloproteinases (MMPs), and a typical proteolytic ADAM protein comprises propeptide, metalloproteinase, disintegrin-like, cysteine-rich, epidermal growth factor-like, transmembranes and cytoplasmic domains (non-patent documents 3-9). Many proteolytic ADAMs, including ADAMS, ADAMS, ADAM12, ADAM15, ADAM17, ADAM19 and ADAM28 are overexpressed in human cancers and are associated with tumor growth and progression (non-patent documents 5, 9). The present inventors' previous studies have indicated that ADAM28 (also known as ADAM metallopeptidase domain 28), which has two alternative isoforms, including a prototype membrane-anchored form (ADAM28m) and a short secreted form (ADAM28s) (non-patent documents 5, 10, 11), is abundantly expressed in human non-small cell lung and breast carcinomas (non-patent documents 12, 13). By in situ hybridization and immunohistochemistry, the present inventors have demonstrated that ADAM28 is expressed predominantly in carcinoma cells contained in carcinoma tissues and that the mRNA expression levels of ADAM28 are associated with the cellular proliferation of breast cancer (non-patent document 13) and with both cancer cell proliferation and infiltration in non-small cell lung cancer (non-patent document 12). In a parallel study, the present inventors showed that serum ADAM27 levels in non-small cell lung cancer patients substantially increase with the progression of tumor, lymph node metastasis, and cancer recurrence (non-patent document 14). These data imply that ADAM28 is involved in cell proliferation and metastasis particularly in human cancer. The present inventors have demonstrated that ADAM28 contributes to cancer cell proliferation through enhanced bioavailability of insulin-like growth factor-I (IGF-I) by selective digestion of IGF-binding protein-3 (IGFBP-3) of IGF-I/IGFBP-3 complex (non-patent document 13), and to angiogenesis by digestion of connective tissue growth factor in breast cancer (non-patent document 15).
The phage display method is one of the display techniques that have realized a in vitro high-speed selection by forming a one-to-one correspondence in the form of phage particles between a functional peptide or protein and a DNA encoding same. This phage display method has been applied to antibody selection, and many antibodies obtained by this method have been developed as medicaments (non-patent document 16).
Furthermore, a method of obtaining a specific antibody by combining a human artificial antibody library and a phage display method has also been established, and such methods have been practicalized by plural companies, as evidenced by HuCAL (Human Combinatorial Antibody Library) of MorphoSys.